PT703915E - XAMONELINE TARTRATO - Google Patents
XAMONELINE TARTRATO Download PDFInfo
- Publication number
- PT703915E PT703915E PT94917567T PT94917567T PT703915E PT 703915 E PT703915 E PT 703915E PT 94917567 T PT94917567 T PT 94917567T PT 94917567 T PT94917567 T PT 94917567T PT 703915 E PT703915 E PT 703915E
- Authority
- PT
- Portugal
- Prior art keywords
- methylpyridine
- hexyloxy
- tetrahydro
- thiadiazol
- xamoneline
- Prior art date
Links
- JOLJIIDDOBNFHW-UHFFFAOYSA-N xanomeline Chemical compound CCCCCCOC1=NSN=C1C1=CCCN(C)C1 JOLJIIDDOBNFHW-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 2
- -1 4-hexyloxy-1,2,5-thiadiazol-3-yl Chemical group 0.000 claims 1
- XCQPLIZWQGDFML-UHFFFAOYSA-N CCCCCCOC1=NSN=C1C1N(C)CCC=C1 Chemical compound CCCCCCOC1=NSN=C1C1N(C)CCC=C1 XCQPLIZWQGDFML-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 238000005185 salting out Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 abstract description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 229940095064 tartrate Drugs 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 238000001914 filtration Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- AAALWAVFSMSWAR-UHFFFAOYSA-N 3-(1,6-dimethyl-3,6-dihydro-2h-pyridin-5-yl)-4-hexoxy-1,2,5-thiadiazole Chemical compound CCCCCCOC1=NSN=C1C1=CCCN(C)C1C AAALWAVFSMSWAR-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000007707 calorimetry Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000472 muscarinic agonist Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines Containing Plant Substances (AREA)
- Compounds Of Unknown Constitution (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
K>3*9té MEMÓRIA DESCRITIVA “XAMONELINE TARTRATO” A presente invenção refere-se a 3-(4-hexiloxi-l,2,5-tiadiazol-3-il)-l,2,5,6-tetrahidro-1 -metilpiridina (+) L-hidrogentartrato cristalino ao que se faz referência no presente documento como Xamoneline tartrato e refere-se deste modo a sua preparação e emprego como agente terapêutico. A patente U.S. Núm. 5,043,345 expõe uma classe de compostos que são agonistas colinérgicos muscarínicos e portanto podem-se empregar de forma terapêutica como estimulantes da função cognitiva especialmente no tratamento da doença de Alzheimer.The present invention relates to 3- (4-hexyloxy-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methyl- methylpyridine (+) L-hydrogentrate hydrochloride referred to herein as Xamoneline tartrate and thus relates to its preparation and use as a therapeutic agent. U.S. Patent No. 5,043,345 discloses a class of compounds which are muscarinic cholinergic agonists and therefore can be therapeutically employed as cognitive function stimulants especially in the treatment of Alzheimer's disease.
No exemplo 9 da patente U.S. Número 5,043,345 descreve-se a preparação de 3-(4-hexiloxi-l,2,5-tiadiazol-3-il)-l,2,5,6-tetrahidro-l- metilpiridina da fórmulaIn example 9 of U.S. Patent Number 5,043,345 the preparation of 3- (4-hexyloxy-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine of formula
I.I.
Na presente solicitude faz-se referência ao composto da figura I com a denominação Xamoneline. 1In the present application reference is made to the compound of figure I with the denomination Xamoneline. 1
Devido a sua basicidade, prefere-se o emprego de Xamoneline como agente terapêutico na forma de um sal de adição ácida. No exemplo 9 da patente U.S. Número 5,043,345, Xamoneline obtém-se como base livre e converte-se posteriormente em sal ácido oxálico.Due to its basicity, the use of Xamoneline as therapeutic agent in the form of an acid addition salt is preferred. In example 9 of U.S. Patent Number 5,043,345, Xamoneline is obtained as the free base and is subsequently converted to oxalic acid salt.
Mas, um sal ácido oxálico não é desejado desde o ponto de vista farmacêutico já que potencialmente pode ter efeitos adversos sobre a função renal do paciente, (.J.Pharm.Sci. 1977, 66 (1), 1-19). Concretamente rejeita-se o emprego de sais ácidos oxálicos para tratar pessoas com idade avançada.However, an oxalic acid salt is not desired from the pharmaceutical standpoint since it may potentially have adverse effects on the patient's renal function (J.J.Pharm.Sci. 1977, 66 (1), 1-19). The use of oxalic acid salts to treat the elderly is specifically rejected.
Além disso, para emprego comercial, é importante dispor de um sal fisiologicamente aceitável com boa bio disposição, boas propriedades de manipulação e com uma forma cristalina reproduzível.Furthermore, for commercial use, it is important to have a physiologically acceptable salt with good bio-disposition, good handling properties and a reproducible crystalline form.
Actualmente descobriu-se que, de uma série de doze ácidos farmacêuticamente aceitáveis, surpreendentemente, só Xamoneline tartrato possui as propriedades desejadas que foram descritas anteriormente.It has now been found that from a series of twelve pharmaceutically acceptable acids, surprisingly, only Xamoneline tartrate has the desired properties which have been described above.
Como consequência disto, a presente invenção fornece Xamoneline tartrato cristalino como um material novo, concretamente numa forma farmaceuticamente aceitável. A presente invenção também fornece uma composição farmacêutica que se compõe de Xamoneline tartrato cristalino compreendendo Xamoneline tartrato cristalino e um suporte farmaceuticamente aceitável. 2As a consequence of this, the present invention provides crystalline Xamoneline tartrate as a novel material, concretely in a pharmaceutically acceptable form. The present invention also provides a pharmaceutical composition comprising crystalline Xamoneline tartrate comprising crystalline Xamoneline tartrate and a pharmaceutically acceptable carrier. 2
As composições desta invenção devem ser adaptadas para uma administração oral, porém as formulas de dissolução para a administração parenteral também se encontram dentro do campo da presente invenção. A composição apresenta-se normalmente como uma composição de dose unitária que contém de 1 a 200 mg, normalmente de 2 a 100 mg, por exemplo de 2 a 50 mg como 2, 4, 8, 10, 20, 25 ou 30 mg. Essa composição é tomada normalmente de 1 a 6 vezes diárias, por exemplo 2, 3 ou 4 vezes diárias de modo que a quantidade total do agente activo administrado se encontra dentro da margem de 4 a 400 mg.The compositions of this invention must be adapted for oral administration, but the dissolution formulas for parenteral administration are also within the scope of the present invention. The composition is usually presented as a unit dose composition containing from 1 to 200 mg, usually 2 to 100 mg, for example from 2 to 50 mg as 2, 4, 8, 10, 20, 25 or 30 mg. Such composition is usually taken 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of the active agent administered is within the range of 4 to 400 mg.
Entre as formas de dosagem unitárias preferidas encontram-se os comprimidos ou as cápsulas. A composição da presente invenção pode-se formular através dos métodos convencionais de aditivo como mistura, recheio e compressão.Among the preferred unit dosage forms are tablets or capsules. The composition of the present invention may be formulated by conventional additive methods such as blending, filling and compression.
Entre os suportes adequados para o emprego na presente invenção encontram-se um diluente, um aglutinante, um desintegrante, um colorante, um agente aromatizante e/ou um conservante. Esses agentes podem utilizar-se convencionalmente, por exemplo de modo parecido ao que já foi empregado com agentes de uso clínico para tratar a doença de Alzheimer. A invenção fornece, além disso, o emprego de Xamoneline tartrato cristalino farmaceuticamente aceitável para tratar a doença de Alzheimer. O Xamoneline tartrato foi sintetizado, purificado e cristalizado como se descreve no exemplo seguinte. 3Suitable carriers for use in the present invention include a diluent, a binder, a disintegrant, a colorant, a flavoring agent and / or a preservative. Such agents may be used conventionally, for example in a manner similar to what has already been employed with agents of clinical use for treating Alzheimer's disease. The invention further provides the use of pharmaceutically acceptable crystalline Xamoneline tartrate for treating Alzheimer's disease. The Xamoneline tartrate was synthesized, purified and crystallized as described in the following example. 3
Exemplo 1 3-(4-Hexiloxi-1,2,5-tiadiazol-3-il)-1,2,5,6-tetrahidro-·1 -metilpiridina (+) L- hidrogentartrato (Xamoneline tartrato) A uma solução de 3-(4-hexiloxi-l,2,5-tiadiazol-3-il)-l-metilpiridinium ioduro (1.00 kg, 2,47 mol) (Patente U.S. Núm. 5,043,345) agitada em metanol (41.) baixo nitrogénio agregou-se-lhe uma solução de borohidruro de sódio (113 g, 2,99 mol) em 0,1 N de hidróxido sádico (500 ml) transcorridas 3 h a 0-5°C. A mistura da reacção agitou-se durante 30 minutos mas antes da neutralização com 4N de ácido hidroclorhídrico (800 ml). O pH ajustou-se entre 7 e 8 e agregou-se água (8 1.) A mistura foi extraída com cloruro de metileno (2x21). Foi lavada com água as fases orgânicas combinadas e forma evaporada para obter a base livre do composto do título com um rendimento de 700 g.Example 1 3- (4-Hexyloxy-1,2,5-thiadiazol-3-yl) -1,2,5,6-tetrahydro-1-methylpyridine (+) L-hydrate tartrate (Xamoneline tartrate) (1.00 kg, 2.47 mol) (U.S. Patent No. 5,043,345) stirred in methanol (41.) under nitrogen added was added a solution of sodium borohydride (113 g, 2.99 mol) in 0.1 N sodium hydroxide (500 ml) over 3 h at 0-5 ° C. The reaction mixture was stirred for 30 minutes but before neutralization with 4N hydrochloric acid (800 ml). The pH was adjusted to between 7 and 8 and water (8 l) was added. The mixture was extracted with methylene chloride (2x21). The combined organic phases were washed with water and evaporated to obtain the free base of the title compound in a yield of 700 g.
Dissolveu-se o resíduo em 2-propanol (2,5 I.) e agregou-se-lhe ácido fumárico (290 g, 2,50 mol). Esquentou-se a mistura até obter uma solução clara, à continuação acrescentou-se-lhe acetona (2,5 1.). Esfriou-se a solução agitada a 5 - 10°C e recolheu-se o sal do fumarato precipitada, através de filtração.The residue was dissolved in 2-propanol (2.5 L) and fumaric acid (290 g, 2.50 mol) was added. The mixture was heated to a clear solution, then acetone (2.5 L) was added. The stirred solution was cooled to 5-10 ° C and the precipitated fumarate salt collected by filtration.
Fez-se a suspensão do precipitado (1 kg, 2,52 mol) em cloruro de metileno (4 1.) e água (2 1.) e acrescentou-se-lhe uma solução de hidróxido sódico (560 ml, 27,65%, 5,04 mol). A mistura da reacção foi agitada até que se obteve uma solução clara, à continuação separou-se a fase de cloruro de metileno e lavou-se duas vezes com água (2 1.).The precipitate (1 kg, 2.52 mol) in methylene chloride (4 L) and water (21 L) was suspended and a solution of sodium hydroxide (560 ml, 27.65 %, 5.04 mol). The reaction mixture was stirred until a clear solution was obtained, then the methylene chloride phase was separated and washed twice with water (2 L).
Filtrou-se a fase orgânica e evaporou-se para obter a base livre do composto do título como um azeite. Este azeite dissolveu-se em 2- propanol (5 1.) e acrescentou-se (+) L-ácido tartárico (416 g, 2.77 mol). A mistura foi esquentada até que se obteve uma solução clara. A solução esfriou lentamente 4 por meio de agitação a 5-10°C e o precipitado foi recolhido através da filtração e secou-se para obter o produto desejado com um rendimento de 980 g (90%). A recristalização a partir de 2-propanol (5 1.) esquentado (80°C) ao que se acrescentou carbono activado (10 g) deu como resultado depois da filtração e do esfriamento a 5-10°C cristais puros do composto do título. Recolheram-se os cristais através da filtração e secaram-se a 40°C para obter 900 g (90%). PF 95,5°C (calorimetria por análise diferencial). 1H-NMR (CD30D, TMS): (7.3 (1H, t), 4.9 (4H, s), 4.5 (2H, t), 4.4 (2H, s), 4.2 (2H, s), 3.4 (2H, t), 3.3 (CH30D), 3.0 (3H, s), 2.7 (2H, q), 1.9 (2H, m), 1.5 (2H, m), 1.4 (4H, m), 0.9 (3H, t). 13C-NMR (.DMSO-d6, TMS): (173.8, 162.0, 145.6, 128.1, 126.7, 72.0, 70.9, 52.8, 49.5, 43.7, 30.7, 28.1, 25.0, 24.3, 21.9, 13.8. MS: 281 (M+).The organic phase was filtered and evaporated to give the free base of the title compound as an oil. This oil was dissolved in 2-propanol (51) and (+) L-tartaric acid (416 g, 2.77 mol) was added. The mixture was heated until a clear solution was obtained. The solution slowly cooled 4 by stirring at 5-10 ° C and the precipitate was collected through filtration and dried to give the desired product in 980 g (90%) yield. Recrystallization from warmed (80 ° C) 2-propanol (50 ° C) to which activated carbon (10 g) was added resulted, after filtration and cooling at 5-10 ° C pure crystals of the title compound . The crystals were collected through filtration and dried at 40 ° C to give 900 g (90%). Mp 95.5øC (differential analysis calorimetry). 1 H-NMR (CD 3 OD, TMS): 7.3 (1H, t), 4.9 (4H, s), 4.5 (2H, t), 4.4 (2H, s), 4.2 (2H, (3H, s), 2.7 (2H, q), 1.9 (2H, m), 1.5 (2H, m), 1.4 (4H, m), 0.9 (3H, t) MS: 281 (M +) MS (ESI +): 238 (M + H +), .
Lisboa, 15 de Dezembro de 2000.Lisbon, 15 December 2000.
Pela Requerente O Agente OficialBy the Applicant The Official Agent
Adjunto do Agente Oficiei de Propriedade IndustrieiDeputy of the Agent Office of Industrial Property
R. D. Jcão V, 9-2.° d<.°- J250 ÍISBOA 5R. D. JOCH V, 9-2, d., J250 ISISB 5
Claims (5)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7257293A | 1993-06-04 | 1993-06-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PT703915E true PT703915E (en) | 2001-03-30 |
Family
ID=22108479
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PT94917567T PT703915E (en) | 1993-06-04 | 1994-05-26 | XAMONELINE TARTRATO |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US5834495A (en) |
| EP (1) | EP0703915B1 (en) |
| JP (1) | JP3190679B2 (en) |
| KR (1) | KR100339115B1 (en) |
| CN (1) | CN1064681C (en) |
| AT (1) | ATE196631T1 (en) |
| AU (1) | AU698673B2 (en) |
| CA (1) | CA2164296C (en) |
| CZ (1) | CZ290550B6 (en) |
| DE (1) | DE69426021T2 (en) |
| DK (1) | DK0703915T3 (en) |
| ES (1) | ES2152315T3 (en) |
| FI (1) | FI955829A (en) |
| GR (1) | GR3035033T3 (en) |
| HU (1) | HUT75038A (en) |
| IL (1) | IL109866A (en) |
| NO (1) | NO305560B1 (en) |
| NZ (2) | NZ267062A (en) |
| PT (1) | PT703915E (en) |
| SK (1) | SK281980B6 (en) |
| WO (1) | WO1994029303A1 (en) |
| ZA (1) | ZA943904B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6117890A (en) * | 1996-08-01 | 2000-09-12 | Eli Lilly And Company | Method for treating bipolar disorder |
| US6043258A (en) * | 1996-08-01 | 2000-03-28 | Eli Lilly And Company | Method for treating disruptive behavior disorders with xanomeline |
| EP0821954A1 (en) * | 1996-08-01 | 1998-02-04 | Eli Lilly And Company | Method for treating mental retardation |
| EP0821956A1 (en) * | 1996-08-01 | 1998-02-04 | Eli Lilly And Company | Method for treating disruptive behavior disorders |
| US6090829A (en) * | 1996-08-01 | 2000-07-18 | Eli Lilly And Company | Method for treating excessive aggression |
| US6034108A (en) * | 1997-07-28 | 2000-03-07 | Eli Lilly And Company | Method for treating mental retardation |
| EP3265128A4 (en) * | 2015-03-06 | 2018-09-12 | Chase Pharmaceuticals Corporation | Oxybutynin transdermal therapeutic system muscarinic agonist combination |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5260311A (en) * | 1989-02-22 | 1993-11-09 | Novo Nordisk A/S | Piperidine compounds and their use |
| US5043345A (en) * | 1989-02-22 | 1991-08-27 | Novo Nordisk A/S | Piperidine compounds and their preparation and use |
| US5264444A (en) * | 1989-02-22 | 1993-11-23 | Novo Nordisk A/S | Piperidine compounds and use |
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1994
- 1994-05-26 CN CN94192681A patent/CN1064681C/en not_active Expired - Fee Related
- 1994-05-26 JP JP50120095A patent/JP3190679B2/en not_active Expired - Fee Related
- 1994-05-26 PT PT94917567T patent/PT703915E/en unknown
- 1994-05-26 DK DK94917567T patent/DK0703915T3/en active
- 1994-05-26 AU AU69242/94A patent/AU698673B2/en not_active Ceased
- 1994-05-26 NZ NZ267062A patent/NZ267062A/en unknown
- 1994-05-26 SK SK1520-95A patent/SK281980B6/en unknown
- 1994-05-26 CA CA002164296A patent/CA2164296C/en not_active Expired - Fee Related
- 1994-05-26 DE DE69426021T patent/DE69426021T2/en not_active Expired - Fee Related
- 1994-05-26 ES ES94917567T patent/ES2152315T3/en not_active Expired - Lifetime
- 1994-05-26 AT AT94917567T patent/ATE196631T1/en not_active IP Right Cessation
- 1994-05-26 WO PCT/DK1994/000205 patent/WO1994029303A1/en active IP Right Grant
- 1994-05-26 EP EP94917567A patent/EP0703915B1/en not_active Expired - Lifetime
- 1994-05-26 KR KR1019950705467A patent/KR100339115B1/en not_active IP Right Cessation
- 1994-05-26 HU HU9503453A patent/HUT75038A/en unknown
- 1994-05-26 CZ CZ19953210A patent/CZ290550B6/en not_active IP Right Cessation
- 1994-06-02 IL IL10986694A patent/IL109866A/en not_active IP Right Cessation
- 1994-06-03 ZA ZA943904A patent/ZA943904B/en unknown
-
1995
- 1995-12-01 NO NO954892A patent/NO305560B1/en not_active IP Right Cessation
- 1995-12-04 FI FI955829A patent/FI955829A/en not_active Application Discontinuation
-
1996
- 1996-11-26 US US08/756,835 patent/US5834495A/en not_active Expired - Fee Related
-
1999
- 1999-07-09 NZ NZ336733A patent/NZ336733A/en unknown
-
2000
- 2000-12-12 GR GR20000402720T patent/GR3035033T3/en not_active IP Right Cessation
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